23.5 Mixed Aldol Reactions

The previous examples of aldol reactions and condensations used a common reactant as both the enolic donor and the electrophilic acceptor. The product in such cases is always a dimer of the reactant carbonyl compound. Aldol condensations between different carbonyl reactants are called crossed or mixed reactions, and under certain conditions such crossed aldol condensations can be effective.

The success of these mixed aldol reactions is due to two factors. First, aldehydes are more reactive acceptor electrophiles than ketones, and formaldehyde is more reactive than other aldehydes. Second, aldehydes lacking alpha-hydrogens can only function as acceptor reactants, and this reduces the number of possible products by half. Mixed aldols in which both reactants can serve as donors and acceptors generally give complex mixtures of both dimeric (homo) aldols and crossed aldols. Because of this most mixed aldol reactions are usually not performed unless one reactant has no alpha hydrogens.

The following abbreviated formulas illustrate the possible products in such a case, red letters representing the acceptor component and blue the donor. If all the reactions occurred at the same rate, equal quantities of the four products would be obtained. Separation and purification of the components of such a mixture would be difficult.

ACH₂CHO + BCH₂CHO + NaOH A–A + B–B + A–B + B–A

To avoid complex reaction mixtures the reactants should be chosen to favor one particular donor/acceptor reaction. Successful mixed aldol reactions usually use one of two combination of factors.

1) A reaction of an aldehyde with no alpha-hydrogens with a ketone that has alpha hydrogens: Aldehydes lacking alpha-hydrogens cannot form an enolate so they can only function as electrophilic acceptor reactants. This reduces the number of possible products by half. Although it would be possible for the ketone to react with itself it is unlikely. Aldehydes are more reactive acceptor electrophiles than ketones. This makes the preferred reaction one with the ketone as an enoloate donor and the aldehyde as an electrophilic acceptor.

The aldol condensation between an aromatic aldehyde with no α-hydrogens and an aliphatic aldehyde or ketone with α-hydrogen is called a Claisen–Schmidt condensation. The reaction product is a highly conjugated α,β‐unsaturated aldehyde or ketone which forms in the more stable (E)-alkene isomer.

The aldol condensation of ketones with aryl aldehydes to form α,β-unsaturated derivatives is called the Claisen-Schmidt reaction.

2) One of the reactants has alpha-hydrogens which are highly acidic: The acidic compound will be preferably converted into an enolate donor which removes the possibility of its carbonyl acting as an electrophilic acceptor. An example is the aldol condensation of ethylacetoacetate and cyclopentanone. Ethylacetoacetate has α-hydrogens which are particularly acidic due to their conjugate base being stabilized by two carbonyl bonds (Section 22.5). Upon reaction with base, ethylacetoacetate is converted to the enolate donor leaving cyclopentanone to be the electrophilic acceptor. This provides one predominant aldol condensation product. In this reaction sodium ethoxide is used as a base to prevent hydrolysis side-reactions with the ester of ethylacetoacetate.

Example 23.5.4  

 

Exercise 23.5.1

Show the reactants required to make the following using a mixed aldol condensation. Indicate those which would be likely to produce a mixture of products.

a)

b)

c)

Answers

a)

b)

c) Because both reactants have α-hydrogens and neither are particularly acidic, the reaction probably will produce a mixture of condensation products.

---